A genome-wide and metabolic analysis determined the adaptive response of Arabidopsis cells to folate depletion induced by methotrexate.
Control of folate homeostasis is essential to sustain the demand for one-carbon (C1) units that are necessary for major biological functions, including nucleotide synthesis and methylation reactions. In this study, we analyzed the genome-wide and metabolic adaptive response of Arabidopsis (Arabidopsis thaliana) cells to folate depletion induced by the antifolate methotrexate. Drug treatment induced a response typical to xenobiotic stress and important changes in folate content and composition. This resulted in a reduction of cell division and primary energy metabolism that was likely associated with perturbation of nucleotide homeostasis. Through a modification of serine metabolism, folate depletion also induced O-acetylserine accumulation and mimicked sulfur deficiency response. The major adaptive response to folate limitation concerned the composition of the folate pool rather than the intracellular level of cofactors. Thus, no significant change in the expression of genes involved in cofactor synthesis, degradation, or trafficking was observed. However, changes in the distribution of C1 derivative pools and increased expression levels for transcripts coding enzymes manipulating C1 moieties in plastids suggested a reorientation of C1 units toward the synthesis of purine and thymidylate. Also, no genomic or metabolic adaptation was built up to counterbalance the major impairment of the methyl index, which controls the efficiency of methylation reactions in the cell. Together, these data suggested that the metabolic priority of Arabidopsis cells in response to folate limitation was to shuttle the available folate derivatives to the synthesis of nucleotides at the expense of methylation reactions.
Loizeau
Karen
K
Laboratoire de Physiologie Cellulaire Végétale, UMR5168 CNRS-CEA-INRA-Université Joseph Fourier Grenoble I, Institut de Recherches en Technologies et Sciences pour le Vivant, CEA-Grenoble, F-38054 Grenoble cedex 9, France.
De Brouwer
Veerle
V
Gambonnet
Bernadette
B
Yu
Agnès
A
Renou
Jean-Pierre
JP
Van Der Straeten
Dominique
D
Lambert
Willy E
WE
Rébeillé
Fabrice
F
Ravanel
Stéphane
S
D000220:Adaptation, Biological / Q000235:genetics*; D017360:Arabidopsis / Q000166:cytology / Q000187:drug effects / Q000378:metabolism*; D002244:Carbon / Q000378:metabolism; D002455:Cell Division / Q000187:drug effects; D004734:Energy Metabolism / Q000187:drug effects; D005492:Folic Acid / Q000378:metabolism*; D015870:Gene Expression / Q000187:drug effects; D020869:Gene Expression Profiling; D018745:Genome, Plant; D006706:Homeostasis; D002955:Leucovorin / Q000494:pharmacology; D008727:Methotrexate / Q000494:pharmacology*; D009711:Nucleotides / Q000378:metabolism; D018087:Plastids / Q000378:metabolism; D012694:Serine / Q000031:analogs & derivatives / Q000378:metabolism; D013431:Sulfates / Q000378:metabolism; D015262:Xenobiotics / Q000494:pharmacology
D009711:Nucleotides; D013431:Sulfates; D015262:Xenobiotics; D012694:Serine; D002244:Carbon; D005492:Folic Acid; C043943:O-acetylserine; D002955:Leucovorin; D008727:Methotrexate